Glaucoma is a major cause of blindness worldwide, and estimated approximately 67 million people suffered from some form of glaucoma. The majority of cases occur as late adult onset (typically over age 40 years) of primary open-angle glaucoma (POAG), which is the most common form of glaucoma and affects approximately 2% in white population and 7% of black population over 40 years old. POAG results in a characteristic visual field changes corresponding to the excavation of the optic disc that is usually associated with an elevation of intraocular pressure (IOP). Normal-tension glaucoma (NTG) is a form of open-angle glaucoma in which typical glaucomatous cupping of the optic nerve head and visual field loss are present but in which there is no evidence of increased IOP over 21 mm Hg at all times. In Japan, prevalence of glaucoma is approximately 3.5% over 40 years old: POAG 0.58% and NTG 2.04%. Prevalence of NTG in Japanese population is high compared with that in other populations. Glaucoma is a multifactorial disorder characterized by a progressive optic neuropathy associated with a specific visual field loss, and results from the interaction of multiple genes and environmental influences, although intraocular pressure (IOP) is a major risk factor for glaucoma.
Risk factors to develop glaucoma include high IOP, age, race, positive family history, myopia, the presence of diabetes or hypertension, and genetic factors. Although the exact pathogenesis of glaucomatous optic neuropathy is remains unclear, it is generally accepted that an increased IOP is a major risk factor. Current treatment for glaucoma consists of interventions which lower IOP. However, in some patients with glaucoma, NTG or advanced stage of POAG, reduction of IOP does not prevent the progression of the disease, indicating that factors other than an increased IOP may be involved in the development or progress of glaucoma.
POAG and NTG are a heterogeneous group of conditions probably with different multi-factorial etiologies resulting in the observed patterns of neuronal loss in the optic disk. The association between glaucoma and the presence of many systemic vascular diseases including low systemic blood pressure, nocturnal dips in blood pressure, hypertension, migraine, vasospasm, and diabetes has been reported. The presence of optic disc hemorrhages in NTG patients suggests that vascular insufficiencies are deeply involved in the development and progression of NTG. A high percentage of patients with POAG receive a wide variety of medications for coexisting disorder. Especially, systemic hypertension was the most common disorder, occurring in 48% of the total population.
Glaucoma-like morphological changes have been reported in patients with Leber's hereditary optic neuropathy (LHON) at the atrophic stage and dominant optic atrophy (DAO). Recently, the inventor has reported optic disc excavation by a quantitative analysis using Heidelberg retinal tomography (HRT) in the atrophic stage of Japanese 15 patients with LHON harboring the 11778 mutation (Mashima Y et. al., Arch Clin Exp Ophthalmol 2003; 241:75-80, the contents of the cited reference are herein incorporated by reference). LHON is a maternally-transmitted eye disease that mainly affects young adult men. Approximately 70% of patients were male. This disease usually causes severe and permanent loss of vision resulting in a visual acuity of less than 0.1. Visual field defects are present as central or cecocentral scotomas. So far more than 20 point mutations of mitochondrial DNA (mtDNA) have been reported in LHON patients worldwide (Brown M D et. al., Clin Neurosci 1994; 2:138-145, the contents of the cited reference are herein incorporated by reference), and more than 80% of LHON patients carry one of three mtDNA mutations at nucleotide position 3460, 11778, or 14484 (Mackey D A et. al., Am J Hum Genet 1996; 59:481-485, the contents of the cited references are herein incorporated by reference). Although NTG patients were tested for the three LHON mutations of mtDNA nucleotide positions 3460, 11778 and 14484, no mutations and no defects in respiratory chain activity in skeletal muscle samples were detected (Brierley E J et. al., Arch Ophthalmol 114:142-146 and Opial D et. al., Graefes Arch Clin Exp Ophthalmol 239:437-440, the contents of the cited references are herein incorporated by reference).
The major difference among LHON patients with one of these mtDNA mutations is in the clinical course. The 3460 and 14484 mutations are associated with better visual prognosis than the 11778 mutation which shows visual recovery rates of only 4% to 7% (Oostra R J et. al., J med Genet 1994; 31:280-286, Riordan-Eva P et. al., Brain 1995; 118:319-337, Mashima Y et. al., Curr Eye Res 1998; 17:403-408, the contents of the cited reference are herein incorporated by reference). However, visual recovery has been documented in some patients with the 11778 mutation and an age of onset in the low teens (Stone E M et. al., J clin Meuro-Ophthalmol 1992; 12:10-14, Zhu D et. al., Am J Med Genet 1992; 42:173-179, Salmaggi A et. al., Intern J Neuroscience 1994; 77:261-266, Oostra R J et. al., Clin Genet 1997; 51:388-393, Mashima Y et. al., Jpn J Ophthalmol 2002; 46:660-667, the contents of the cited references are herein incorporated by reference). Recovery of vision appears to be more likely when visual deterioration begins at an early age, even in patients with the 11778 mutation.
The clinical variability of LHON patients, which includes age at onset, male predilection, incomplete penetrance, and visual recovery, suggests that the disease most likely results from polygenic or multifactorial mechanisms, possibly involving environmental stressors, X-chromosomal loci, and other mtDNA mutations (Man P Y W et. al., J Med Genet 2002; 39:162-169, the contents of the cited reference are herein incorporated by reference). However, attempts to identify a relevant locus on the X-chromosome have not been successful (Chalmers R M et. al., Am J Hum Genet 1996; 59:103-108 and Pegoraro E et. al., Am J Med Genet 2003; 119A:37-40, the contents of the cited reference are herein incorporated by reference). So-called “secondary LHON mutations” are more frequently found in European LHON patients than in unaffected Europeans and are polymorphisms linked to the European haplotype J. These polymorphisms are not strong autonomous risk factors (Brown M D et. al., Am J Hum Genet 1997; 60:381-387 and Torroni A et. al., Am J Hum Genet 1997; 60:1107-1121, the contents of the cited reference are herein incorporated by reference).
Thus, the primary mutations are the major risk factors in LHON, but additional etiologic factors that augment or modulate the pathogenic phenotypes appear to be necessary. Considerable evidence indicates that heavy alcohol and/or tobacco use increases the risk of optic neuropathy in LHON families (Smith P R et. al., Q J Med 1993; 86:657-660, Chalmers R M et. al., Brain 1996; 119:1481-1486 and Tsao K et. al., Br J Ophthalmol 1999; 83:577-581, the contents of the cited reference are herein incorporated by reference), although one study did not find this association. Possible secondary genetic interactions are complex and not firmly established (Kerrison J B et. al., Am J Ophthalmol 2000; 130:803-812, the contents of the cited reference are herein incorporated by reference).
Oxidative stress has been implicated in many disorders associated with mutations of mtDNA. A recent investigation in an animal model identified reactive oxygen species (ROS) as a likely factor in the pathogenesis of LHON (Qi X et. al., Invest Ophthalmol Vis Sci 2003; 44:1088-1096, the contents of the cited reference are herein incorporated by reference). Additionally, the mtDNA LHON pathogenic mutations were found to predispose cells to Fas-dependent apoptotic death in vitro (Danielson S R et. al., J Biol Chem 2002; 277:5810-5815, the contents of the cited reference are herein incorporated by reference). These findings implied that there must be some nuclear modifier genes involved for developing LHON.